Water soluble nanoparticles of hydrophilic and hydrophobic active materials and an apparatus and method for their production

Abstract

This invention provides a soluble nano-sized particles formed of a core (water-insoluble lipophilic compound or hydrophilic compound) and an amphiphilic polymer and which demonstrated improved solubility and / or stability. The lipophilic compound within the soluble nano-sized soluble (“solu-nanoparticles”) may consist of pharmaceutical compounds, food additives, cosmetics, agricultural products and veterinary products. The invention also provides novel methods for preparing the nano-sized soluble particles, as well as a novel chemical reactor for manufacturing an inclusion complex comprising the nano-sized soluble particles.

Description

FIELD OF THE INVENTION[0001]The invention is in the field of nanoparticles. More particularly, the invention relates to soluble nano-sized particles (“solu-nanoparticles”) and methods of producing solu-nanoparticles that render insoluble compounds solubilized in a medium otherwise not soluble.BACKGROUND OF THE INVENTION[0002]Two formidable barriers to effective drug delivery and hence to disease treatment, are solubility and stability. To be absorbed in the human body, a compound has to be soluble in both water and fats (lipids). Solubility in water is, however, often associated with poor fat solubility and vice versa.[0003]Over one third of drugs listed in the U.S. Pharmacopoeia and about 50% of new chemical entities (NCEs) are insoluble or poorly insoluble in water. Over 40% of drug molecules and drug compounds are insoluble in the human body. In spite of this, lipophilic drug substances having low water solubility are a growing drug class having increasing applicability in a vari...

AI Technical Summary

Benefits of technology

[0032]Soluble nanoparticles, referred to as “solu-nanoparticles” in accordance with the present invention are differentiated by the use of water soluble amphiphilic polymers that are capable of producing molecular complexes with lipophilic and hydrophilic active compounds or molecules (particularly, drugs and pharmaceuticals). The solu-nanoparticles formed in accordance with the present invention render insoluble compounds soluble in water and readily bioavailable in the human body.

[0033]In accordance with the present invention, the solu-nanoparticles are comprised of polymers having an active compound or molecule wrapped and fixated or secured within the polymer. The solu-nanoparticles involve the active compound or molecule, which is linked with the polymer by non-valent bonds and form a polymer-active compound as a distinct molecular entity. The outer surface of the solu-nanoparticles is comprised of a polymer that carries the drug molecule to the target destination. The complex may be nano-level in size, and no change occurs in the drug molecule itself when it is enveloped, or advantageously wrapped, by the polymer. The solu-nanoparticle remains stable for long periods of time, may be manufactured at a low cost, and may, improve the overall bioavailability of the active compound.

[0034]The polymer used in the formation of these complexes is selected from the group of amphiphilic polymers that demonstrate hydrophilic-lipophilic balance (HLB) so that the sum total HLB of the complex allows for water solubility with stable solutions of nano-emulsions or nano-suspensions. The amphiphilic polymer is selected using an algorithm that takes into account the molecular weight, the dimensions (in three directions), the surface polarity and the solubility in non-aqueous solvents of the lipophilic or hydrophilic compound. Unlike prior art inclusion complexes, the inclusion complex of the present invention imposes no limitations upon the size of the core compound that can be used. The conditions during the process of forming the nano-soluparticles are such that they do not lead to the destruction of the molecular composition of the core active lipophilic or hydrophilic compound or to the loss of its physiological or biological activity. With regard to the process of preparing the inclusion complexes of the present invention, the process temperature is always lower than the temperature at which the lipophilic compound is losing its physiological or biological activity, or the temperature at which the lipophilic composition changes its chemical composition.

[0035]Depending upon the polymer used in the formation of the solu-nanoparticles, drugs and pharmaceuticals as the active compound within the complex, are able to reach specific areas of the body readily and quickly. The polymer and active compound selected will also provide solu-nanoparticles capable of multi-level, multi-stage and / or controlled release of the drug or pharmaceutical within the body.

[0036]A significant advantage and unique feature of the complex (inclusion or other) of present invention is that no new bonds are formed and no existing bonds are destroyed during the formation of the inclusion complex. Additionally, existing conditions during the addition of the active compound into the formulation of this complex assures the creation of soluble nanoparticles. Furthermore, the ingredients used in the preparation of the complex are inexpensive, abundant, non-toxic and safe for use in the surrounding environment.

[0037]In another aspect of the present invention, a novel chemical reactor apparatus is provided for carrying out the method of forming the solu-nanoparticles in accordance with the present invention. The chemical reactor of the present invention provides for continuous circulation of a “carrier” between the polymer solution and the active compound during the production of the complex of the present invention. This ensures a high uniformity of the emulsion or the suspension formed during the process. The design of the chemical reactor allows all of the processes to occur in the same vessel, thus ensuring high purity in the final product and also simplifying the process and reducing the labor required.

Problems solved by technology

Two formidable barriers to effective drug delivery and hence to disease treatment, are solubility and stability.

Solubility in water is, however, often associated with poor fat solubility and vice versa.

Each of the existing companies focusing on these large and small molecules has its own restriction and limitations with regard to both large and small molecules on which they focus.

Solubility and stability issues are major formulation obstacles hindering the development of therapeutic agents.

These formulations are often irritating to the patient and may cause adverse reactions.

At times, these methods are inadequate for solubilizing enough of a quantity of a drug for a parenteral formulation.

Overdosage does, however waste a large amount of the active compound.

Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water.

Although a number of solubilization technologies do exist, such as liposomes, cylcodextrins, microencapuslation, and dendrimers, each of these technologies has a number of significant disadvantages.

However, common problems encountered with liposomes include: low stability, short shelf-life, poor tissue specificity, and toxicity with non-native lipids.

Additionally, the uptake by phagocytic cells reduces circulation times. Furthermore, preparing liposome formulations that exhibit narrow size distribution has been formidable challenge under demanding conditions, as well as a costly one.

Also, membrane clogging often results during the production of larger volumes required for pharmaceutical production of a particular drug.

For a long time most cyclodextrins had been no more than scientific curiosities due to their limited availability and high price.

The disadvantages of the cyclodextrins, however, include: limited space available for the active molecule to be entrapped inside the core, lack of pure stability of the complex, limited availability in the marketplace, and high price.

The relatively high production cost needed for many of the formulations is, however, a significant disadvantage.

Problems associated with the use of polymers in micro- and nanoencapsulation include: the use of toxic emulgators in emulsions or dispersions, polymerization or the application of high shear forces during emulsification process, insufficient biocompatibility and biodegrability, balance of hydrophilic and hydrophobic moieties, etc.

These characteristics lead to insufficient drug release.

However, dendrimer technology is still in the research stage, and it is speculated that it will take years before the industry will apply this technology as a safe and efficient drug delivery system.

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